Dengue hemorrhagic fever and shock syndromes*

Suchitra Ranjit, MBBS, MD; Niranjan Kissoon, MBBS, FAAP, FCCM, FACPE

Dengue viral infections affectall age groups and produce aspectrum of clinical illnessthat ranges from asymptom-

atic to a mild or nonspecific viral syn-drome to a severe and occasionally fataldisease characterized by shock and hem-orrhage (1, 2). Dengue fever (DF) is anold disease; the first record of a clinicallycompatible disease was documented in aChinese medical encyclopedia in 992 (3).This illness has reemerged in the last 3–4decades with an expanded geographic dis-tribution of both the viruses and the mos-quito vectors (1, 2, 4–6); in 1998, denguewas recognized as the most importanttropical infectious disease after malaria

(1, 2, 4–6). The disease is encounteredvirtually throughout the tropics, and the2005 World Health Assembly resolutionincluded dengue as an example of a dis-ease that may constitute a public healthemergency of international concern withimplications for health security due torapid epidemic spread beyond nationalborders (2).

In this article we review the epidemi-ology, immunopathogenesis, clinical syn-dromes, diagnosis, management, andprevention of dengue.

Method

Boolean searches were carried out byusing PubMed from 1975 to March 2009and the Cochrane Database of SystematicReviews from 1993 to December 2009 toidentify potentially relevant articles bykey search terms such as: “dengue”; “den-gue fever”; “dengue hemorrhagic fever”;“dengue shock syndrome”; “dengue” and“immunopathogenesis,” pathogenesis,”“classification,” “complications,” “man-agement,” and “prevention.” We alsosearched the extensive bibliography listsof the relevant articles. Case reports were

considered only if pertinent. Only En-glish-language articles were included.

We considered the most relevant arti-cles that would be important and of in-terest to the critical care practitioner. Inparticular, we attempted to find meta-analyses or well-designed randomized,controlled trials to support a recommen-dation for intervention and treatment.When none was available, we cited anauthoritative consensus statement or aclinical guideline such as those from ma-jor medical organizations or interna-tional health agencies and bodies such asthe World Health Organization (WHO)and the Centers for Disease Control andPrevention.

Epidemiology

In the past 50 yrs, the prevalence ofDF has increased 30-fold, and significantoutbreaks have occurred in five of sixWHO regions. It is now endemic in 112countries; Southeast Asia and the west-ern Pacific have the most serious afflic-tions (4, 5, 7). Case fatality rates varyfrom 1% to 5% (8) but can be �1% withappropriate treatment (2). The reasonsfor the global resurgence of epidemics of

*See also p. 116.From the Pediatric Intensive Care Unit (SR), Apollo

Children’s Hospital, Chennai, India; Department of Pe-diatrics (NK), BC Children’s Hospital, Vancouver, BC,Canada.

The authors have not disclosed any potential con-flicts of interest.

For information regarding this article, E-mail:nkissoon@cw.bc.ca

Copyright © 2011 by the Society of Critical CareMedicine and the World Federation of Pediatric Inten-sive and Critical Care Societies

DOI: 10.1097/PCC.0b013e3181e911a7

Objectives: To provide a comprehensive review of dengue, withan emphasis on clinical syndromes, classification, diagnosis, andmanagement, and to outline relevant aspects of epidemiology,immunopathogenesis, and prevention strategies. Dengue, a lead-ing cause of childhood mortality in Asia and South America, is themost rapidly spreading and important arboviral disease in theworld and has a geographic distribution of >100 countries.

Data Source: Boolean searches were carried out by usingPubMed from 1975 to March 2009 and the Cochrane Database ofSystematic Reviews from 1993 to March 2009 to identify potentiallyrelevant articles by key search terms such as: “dengue”; “denguefever”; “dengue hemorrhagic fever”; “dengue shock syndrome”;“severe dengue” and “immunopathogenesis,” pathogenesis,” “clas-sification,” “complications,” and “management.” In addition, au-thoritative seminal and up-to-date reviews by experts were used.

Study Selection: Original research and up-to-date reviews andauthoritative reviews consensus statements relevant to diagnosisand therapy were selected.

Data Extraction and Synthesis: We considered the most rele-vant articles that would be important and of interest to the critical

care practitioner as well as authoritative consensus statementsfrom the World Health Organization and the Centers for DiseaseControl and Prevention. Dengue viral infections are caused by oneof four single-stranded ribonucleic acid viruses of the familyFlaviviridae and are transmitted by their mosquito vector, Aedesaegypti. The clinical syndromes caused by dengue viral infectionsoccur along a continuum; most cases are asymptomatic and fewpresent with severe forms characterized by shock. Managementis predominantly supportive and includes methods to judiciouslyresolve shock and control bleeding while at the same time pre-venting fluid overload.

Conclusions: Dengue is no longer confined to the tropics andis a global disease. Treatment is supportive. Outcomes can beoptimized by early recognition and cautious titrated fluid replace-ment, especially in resource-limited environments. (Pediatr CritCare Med 2011; 12:90–100)

KEY WORDS: dengue hemorrhagic fever; dengue shock syn-drome; shock; immunopathogenesis; diagnosis; management;children; critical illness

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dengue are complex and include large-scale population migration, increased airtravel, unprecedented global populationgrowth, and uncontrolled urbanization,all of which facilitate transmission andincrease densities of Aedes (Ae.) aegypti–borne disease (5, 6, 9). Dengue has alsobeen transmitted via blood transfusionand organ transplantation (10).

Dengue Viruses. There are four closelyrelated but serologically distinct dengueviruses (DVs), members of the Flavivirusgenus of the Flaviviridae, called DEN-1,DEN-2, DEN-3, and DEN-4. Lifetime im-munity follows infection by one serotype,but immunity to the other serotypes isshort-lived (11, 12).

Mosquito Vectors. Mosquitoes that be-long to the genus Aedes play a pivotal rolein the transmission of dengue. The prin-cipal vector is Ae. aegypti, but Ae. albop-ictus and Ae. polynesiensis may act asvectors depending on the geographic lo-cation (6, 12).

Viral Replication and TransmissionCycle of DV. Both epidemic and endemictransmission of DV are maintainedthrough a human-mosquito-human cyclein which humans are the amplifying host.DV is introduced into the skin by the biteof an infected female Aedes mosquito.Viremia in susceptible humans begins be-tween 3 and 6 days after subcutaneousinjection, lasts for another 3–6 days, andends as the fever resolves (6, 13, 14).Dengue can essentially be excluded as thecause of symptoms in a traveler who de-velops an illness �14 days after returningfrom a dengue-endemic country (15).

Immunopathogenesis of DVInfections

The immunopathogenesis of severeDV infections is complex and remains in-completely understood; however, severedengue is differentiated from its milderforms by the presence of increased vascu-lar permeability (1, 2, 9, 12). A few salientfeatures may explain the dramatic clinicalmanifestations.

T-Cell Activation and Apoptosis. In-tense T-cell activation and massive apo-ptosis may lead to the sudden onset ofvascular permeability and hemorrhagethat characterizes severe forms of denguedisease (12). In some patients with sec-ondary dengue infections, however, theT-cell response may cause suboptimalkilling of the DV-infected monocytes andserve to augment the severity of the sec-ond infection due to higher viral loads(12, 16).

Neutralizing Antibodies and Antibody-Dependent Enhancement. The severity ofsecondary infection with a different DVserotype depends on the balance betweenneutralizing vs. enhancing heterotypicantibodies after the first infection. Thisphenomenon has been called “antibody-dependent enhancement” and is one ofthe best known hypotheses in the im-munopathogenesis of severe dengue (9,17–19).

Factors that Influence DiseaseSeverity

Most DV infections produce, in de-creasing order of frequency, an asymp-tomatic infection, mild nonspecific symp-toms, or classic dengue (1, 9). The moresevere manifestations of shock and hem-orrhage occur in �5% of DV infections(9, 11). Complex, interlinked mecha-nisms determine whether mild or severedisease occurs (9).

Primary vs. Secondary Infection. Thegreatest risk factor for the developmentof severe dengue is secondary infectionwith a different dengue serotype from theoriginal infecting virus (9, 11, 12). Severeillness during secondary dengue infec-tions was associated with higher peakplasma virus titers (20).

Age. Dengue hemorrhagic fever (DHF)is primarily a disease of infants and chil-dren (1, 9), although adults may also beafflicted with severe disease (21). Infantscan develop features of severe diseaseeven during a primary DV infection whentheir transplacentally acquired maternal

antibody levels decline below the neutral-ization threshold (12, 22, 23).

Nutritional Status. Unlike other infec-tious diseases, severe forms of dengue aremore common in well-nourished children,and grade 2 or 3 protein-calorie malnutri-tion protects against severe dengue vascu-lopathy. This negative association may berelated to suppression of cellular immunityin malnutrition (11, 24).

Classification and ClinicalCourse of Dengue

The widely used 1997 WHO classifica-tion grouped patients with symptomaticdengue infections into three categories: un-differentiated fever; DF; and DHF (1) (Fig. 1).

However, with dengue being encoun-tered in newer geographical areas, con-siderable overlap between the groups hasbeen reported, and it is likely that thevarious categories exist as a continuumrather than separate entities (2, 9, 25–27). Similarly, the classification inher-ently assumed that DF was a mild diseaseand that only cases of DHF were severe;thus, patients even with severe and life-threatening manifestations of denguecould not be included as having DHFunless all criteria were present. This hadadverse effects at various levels, includingduring triage, disposition, and treatmentdecisions, the urgency of which was dic-tated by the severity classification of den-gue (25). Furthermore, the term “DHF”puts undue emphasis on hemorrhage;however, the hallmark of severe dengue(and the manifestation that should be ad-dressed early) is not hemorrhage but in-creased vascular permeability, whichleads to shock (12). Authors of a WHO/Tropical Disease Research–supported,prospective, clinical, multicenter studyacross dengue-endemic regions proposeda revised and simplified dengue case clas-sification in a move to help cliniciansidentify rapidly and treat adequately themost severe, life-threatening forms of thedisease (2, 28).

The new system divides dengue casesinto just two major categories of severity: a)dengue (with or without warning signals);and b) severe dengue (2, 28) (Fig. 2).

Clinical Manifestations and Phases.Dengue is a systemic and dynamic diseasewith a wide spectrum of clinical presen-tations that range from mild to severe;however, the clinical evolution and out-come may be highly unpredictable.

The course of illness is characterizedby three well-demarcated phases: febrile;Figure 1. The traditional 1997 World Health Organization classification of dengue (1).

91Pediatr Crit Care Med 2011 Vol. 12, No. 1

critical; and recovery (2). Although mostpatients recover after a self-limiting, non-severe, clinical course, a small proportionprogress to have severe disease, which ischaracterized by plasma leakage with orwithout hemorrhage (2).

Clinical Phases of Dengue. After theincubation period, the illness beginsabruptly and is followed by the threephases (Fig. 3).

Phase 1: The febrile phase. Typically, apatient develops a high-grade fever that

lasts 2–7 days and is acutely unwell withheadache, diffuse erythema, generalizedmyalgia, and arthralgia; anorexia, nausea,and vomiting are also common. Youngerchildren may develop febrile seizures. Itmay be difficult to distinguish dengueclinically from other viral fevers, al-though demonstration of microvascularfragility by a positive tourniquet-test re-sult increases the likelihood that it isdengue (2). Frequent meticulous moni-toring for warning signs and other clini-

cal parameters (Fig. 2) is crucial for rec-ognizing progression to the criticalphase. Although a tender hepatomegalyand mild hemorrhagic manifestations(petechiae and mucous membrane bleed-ing from nasal or oral cavity) may be seenoften, significant bleeding episodes fromthe gastrointestinal tract or menorrhagiaare uncommon occurrences in the febrilephase. The earliest laboratory abnormal-ity is a progressive leukopenia, which isanother clue to the presence of probabledengue.

Phase 2: The critical phase. The criti-cal phase begins around the period ofdefervescence, when several importantoccurrences mark their presence in quicksuccession. Leukopenia progresses fur-ther, and a rapid decrease in plateletcount usually occurs. This precedes themost specific and life-threatening mani-festation of this phase: an increase incapillary permeability that leads toplasma leakage and an equivalent rise inhematocrit (Hct).

Plasma leakage begins during the fe-brile phase, but at a time when the viralload and body temperature are declining,and develops rapidly over a period ofhours. The period of plasma leakage isshort-lived, typically lasting 24–48 hrs.However, the extent of plasma loss ishighly variable and is the key that deter-mines the clinical severity in the criticalphase (i.e., whether the patient recoversuneventfully, develops dengue with warn-ing signs, or, in a small proportion withextensive plasma leak, progresses to have“severe dengue”).

Some patients with a nonsevere formof dengue do not develop plasma leak andsteadily improve after defervescence.

Prolonged uncorrected shock, meta-bolic acidosis, and thrombocytopeniamay worsen disseminated intravascularcoagulation, which may, in turn, lead tomassive hemorrhage, thus setting off aprogressive downward spiral of worseshock and hemorrhage (1, 11, 12, 29);these patients are at high risk of death.

Apart from shock and hemorrhage,other important consequences of in-creased capillary permeability arehemoconcentration, hypoalbuminemia,and serous fluid collections, usually pleu-ral effusions and ascites, the extent ofwhich depends both on the magnitude ofplasma leak and the volume of fluids con-sumed or prescribed (1, 2).

Early confirmation of plasma leakagein the critical phase may be provided byserial laboratory studies with complete

Figure 2. New simplified classification of dengue viral infections, World Health Organization 2009.CNS, central nervous system.

Figure 3. Phases of dengue in relation to symptoms and laboratory changes. AST, aspartate transam-inase; ALT, alanine aminotransferase; CNS, central nervous system; IgM, immunoglobulin M; IgG,immunoglobulin G. Adapted with permission from World Health Organization: Dengue HemorrhagicFever: Diagnosis, Treatment, Prevention and Control. Third Edition. Geneva, WHO/TDR, 2009.

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blood counts demonstrating the triad ofprogressively increasing Hct, leukopenia,and thrombocytopenia, ultrasound find-ings of a thickened gall bladder wall, andascitic and pleural fluid and chest radio-graph showing pleural effusions (1, 2).These findings are useful for triage andtherapy because they may be presentmuch earlier than signs of plasma lossare clinically manifest and also indicateprogress to the critical phase in patientswho do not defervesce despite the onsetof plasma leakage (2, 11, 12). Evaluatinghemoconcentration in patients with pre-existing anemia may be difficult, becausethe preillness Hct level may be unavail-able at the time of admission. Using thepopulation baseline may be useful (2),such as a cutoff Hct value (36%) in Indianchildren due to the high prevalence ofiron-deficiency anemia (30).

Phase 3: The recovery phase. After thecritical 24 – 48 hrs of plasma leakage,the final recovery phase is heralded by thegradual resorption of the leaked plasmaback into the intravascular compartmentover the next 48–72 hrs. The patient mayexhibit dramatic improvement with anoverall sense of well-being, improved ap-petite, a stable hemodynamic status, anda brisk diuresis. Pruritis and an asymp-tomatic bradycardia may be marked (1,2). The blood picture reflects the recoveryphase with a lower Hct level on accountof the reabsorbed fluid and a white cellincrement that may precede platelet re-covery.

Recognition of this phase is importantso that intravenous (IV) fluids may bepromptly ceased. This simple interven-tion may prevent fluid overload (FO),which, along with severe hemorrhage, isan important, preventable cause of deathby dengue (Fig. 3).

Features of Severe Dengue. Severedengue occurs in a small proportion ofpatients and is defined by one or more ofthe following: 1) shock due to plasmaleakage, which is usually associated withfluid accumulation and consequent respi-ratory symptoms; 2) severe bleeding; and3) severe organ impairment (liver, neu-rologic symptoms, renal or myocardialdysfunction) (Fig. 2) (2, 28).

1) Shock in severe dengue. The hypo-volemic shock in dengue may initially becompensated with a normal systolicblood pressure (BP), elevated diastolicBP, narrow pulse pressure, and featuresof hypoperfusion, such as cold mottledskin, although in some patients, signifi-cant tachycardia may be absent (31). Dif-

ficulties in successful treatment of severedengue stem from the dynamicity of den-gue, which makes it a challenge to detectand manage, especially for the uniniti-ated physician—even experienced clini-cians may be caught unaware. It is thisdynamicity that may account for delays inrecognition of the severity of circulatorycompromise, which can be subtle: sys-tolic BP may be maintained until late,and patients even in advanced shock of-ten remain alert (1, 2).

As shock progresses, the diastolic BPsand then the systolic BPs become unre-cordable, and if they are not promptlyreversed, the patient may progress tohave multiorgan failure and a compli-cated course.

2) Bleeding and hemorrhagic manifes-tations in severe dengue. Common sitesare from the gastrointestinal tract mani-festing as hematemesis or melena (2, 32,33). However, even with severe dengue,in which marked thrombocytopenia andcoagulation abnormalities are frequent(34, 35), major life-threatening bleeds arerare: the most important risk factor forsignificant hemorrhage is prolongedshock, especially when complicated byacidosis and hypoxia (2, 29, 36). Otherrisk factors for bleeding are the presenceof hepatic and/or renal dysfunction (2);drug (e.g., nonsteroidal anti-inflamma-tory drug) exposure; and procedures suchas nasogastric tube insertion, arterialpuncture, or intramuscular injections.

3) Severe organ impairment. Severeorgan impairment is the third criteria forsevere dengue (37) and includes acuteliver failure, encephalopathy/encephali-tis, renal failure, and myocardial dysfunc-tion. These may also contribute to mor-tality and may occur even in the absenceof severe plasma leakage or shock (2).Liver failure may be caused by a directviral effect with hepatitis or focal necrosisof the liver and is associated with a highmortality rate (37, 38). Elevated transam-inase levels have been documented to oc-cur as part of dengue (1) and also afterresuscitation from shock (ischemic hep-atitis) (38).

Neurologic complications. Patientswith severe dengue may present with awide variety of neurologic manifestationsincluding encephalopathy, seizures, andacute pure motor weakness (11, 32, 38,39). The DV has been isolated from thecerebrospinal fluid of some patients hav-ing features of encephalitis (40). In thecritical phase, cerebral hypoperfusionmay result in altered mental status, con-

vulsions, and extensor posturing; theseneurologic signs can improve when theperfusion normalizes. Other causes ofcentral nervous system symptoms in thepatient with severe dengue are coexistingcentral nervous system infections (bacte-rial, viral, or malarial), dengue encepha-lopathy/encephalitis, electrolyte disor-ders, intracranial hemorrhage, andfulminant hepatic failure (38). During re-covery, cerebral edema from FO may leadto obtundation and seizures. The precisecause may be difficult to separate andrequires a consideration of the phase ofdengue and thorough clinical examina-tion in conjunction with laboratory andradiologic investigations to rule out sys-temic causes, electrolyte derangements,and specific organ insults.

Cardiac dysfunction. Plasma leakageand/or hemorrhage causing hypovolemiaand a compensatory elevated systemicvascular resistance are the predominantmechanisms of shock in severe dengue(2, 31). Although primary myocardial in-sult in dengue is infrequent, there havebeen a few reports of relative bradycardiacontributing to low cardiac output (31)and acute ST-segment and T-wavechanges on electrocardiogram, togetherwith low ejection fractions and global hy-pokinesia on radionuclide ventriculogra-phy (41, 42). No myocardial necrosis wasdetected in any of the patients, whichsuggests that myocardial dysfunctionmight either be attributable to humoralfactors or coronary hypoperfusion (43).Both systolic and diastolic dysfunctionhave been reported to cause refractoryshock (38, 44).

Other complications include hemo-lytic uremic syndrome (1, 32) and coin-fections in endemic areas (malaria, lepto-spirosis, enteric fever) (1, 38). Althoughsevere abdominal pain presenting as asurgical emergency had been previouslyclassified as an uncommon manifestation(32), severe intense abdominal pain isnow recognized as one of the most im-portant warning signs heralding signifi-cant plasma leakage and imminentshock. Dengue has also been described asan important cause of hemophagocyticlymphohistiocytosis (45) and pediatricmultiorgan failure (46, 47).

Diagnosis

Although the diagnosis of acute DVinfection is mainly clinical (1), pediatriccaregivers frequently find making anearly diagnosis challenging, because the

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initial symptoms are often nonspecific,many common tropical infections can re-sult in a presentation with fever andthrombocytopenia with or without shock,viremia may be below detectable levels,and serological tests confirm dengue onlylate in the course of illness (2, 48). Per-forming a tourniquet test at each visitmay help differentiate dengue from otherviral infections. Taking note of the tem-poral sequence of symptoms is as impor-tant as recording their presence, becausewith dengue, it is at the time of deferves-cence that the disease manifests its sever-ity, unlike other viral illnesses for whicha clinical improvement is to be expectedwith a decline in body temperature (2).Ramos et al (49) have attempted to iden-tify the clinical features that predict alaboratory-positive dengue infection andconcluded that the presence of high-grade fever, rash, petechiae, or mucosalbleeds in the absence of cough and otherrespiratory symptoms has a very highpositive predictive value of confirmeddengue infection.

Differential Diagnosis. In addition tobacterial septic shock, the differential di-agnoses that must be considered in theappropriate epidemiologic settings in-clude malaria, leptospirosis, typhoid fe-ver, and meningococcal septic shock (1,2, 11). Confusion may also arise when apatient with suspected dengue presentswith central nervous system symptoms.Although central nervous system symp-toms may result from the dengue viralinfection or complications detailed previ-ously, coinfections are not uncommon,and if the clinical or laboratory featuresare atypical for dengue, or coexisting in-fections cannot be ruled out, appropriateempirical antimicrobials (antibiotics, an-tiviral agents, or antimalarial agents)should be initiated after drawing samplesfor laboratory confirmation and appropri-ate cultures.

The choice of antimicrobials dependson the patient’s symptoms and signs,prevalent infections in the community,and their resistance patterns. Early em-pirical antibiotics for suspected septicshock or central nervous system infec-tions are important, because delays ininitiation of appropriate antibiotics havebeen shown to worsen outcomes (50).Cranial imaging may be necessary in thepresence of a neurologic presentation.Performing a lumbar puncture may behazardous in a bleeding, thrombocytope-nic patient in whom the hemodynamicsis precarious (51). A lumbar puncture to

determine any concurrent central ner-vous system infection may be more safelyperformed when the patient is stable.Empirical antimicrobials may be deesca-lated once the clinical picture emergeswith greater clarity and culture resultsare available.

Laboratory Confirmation of Dengue.There are three main methods for diag-nosing DV infections (1, 9, 12, 48): sero-logical tests; virological diagnosis; andmolecular methods including the poly-merase chain reaction. The choice of testdepends on whether the patient is in theinitial stage, in which fever and viremiaare present (virological and molecular di-agnosis most appropriate), or the post-pyrexial period, which lasts a few weeks(serological tests appropriate) (12).

Viral Isolation and Identification byUsing Mosquito Cell Lines. Serum inoc-ulation either into mosquito cell lines ordirectly into mosquitoes is the most com-mon method for virus isolation (9).

Molecular Diagnosis. The sensitivity,specificity, and rapid detection of minutequantities of dengue viral material in thepatient’s serum makes reverse-tran-scriptase polymerase chain reaction use-ful for the detection of dengue infectionearly in the disease (within 48 hrs) whenantibodies are not detected (52). A re-cently available test that can diagnosedengue within the first few days of fever isthe nonstructural protein-1 monoclonalantibody in an enzyme-linked immu-nosorbent assay format that can detectdengue nonstructural protein-1 antigenin blood (12, 53).

Serologic Testing. Confirmation ofacute DV infection is most frequently ac-complished by using serology (1, 2). Se-rologic tests for the diagnosis of acute DVinfection include the hemagglutinationinhibition assay and immunoglobulin G(IgG) or IgM enzyme immunoassays (52).The IgM antibody-capture enzyme-linkedimmunosorbent assay is the test mostwidely used, because it is relatively inex-pensive, sensitive, and quick and simpleto perform; however, it suffers from lowsensitivity compared with the hemag-glutination-inhibition assay (11, 32).The development of several rapid diag-nostic kits, which use immunochro-matographic or immunoblot technolo-gies, has enabled rapid bedsideserological testing; however, the diag-nostic accuracy may be low in terms ofsensitivity and specificity (9, 54).

Laboratory Studies to Monitor Dis-ease Progression and Complications. The

earliest evidence of plasma leak in thecritical phase of dengue as alluded toearlier may be obtained by serial bloodcounts that demonstrate an increasingHct level, progressive leukopenia andthrombocytopenia, and ultrasound find-ings of a thickened gall bladder wall, aswell as ascitic and pleural fluid (Table 1)(2, 12, 55). If formal laboratory servicesare unavailable, a microcentrifuge can beused to estimate capillary Hct at the bed-side. Other tests may be dictated by theclinical status and include measurementsof glucose, electrolytes, blood gases, andlactate and tests of renal, liver, and coag-ulation function.

Management of Patients WithDengue

For such a complex, dynamic, and un-predictable disease, successful outcomeswith mortality rates of �1% can beachieved in the vast majority of patientswith surprisingly simple and inexpensiveinterventions, provided they are early, ap-propriate, and continuously targeted tokeep pace with the disease evolution. Thisunderscores the vital importance of em-powering the front-line healthcare per-sonnel (doctors and nurses) at primaryand secondary health centers, clinics, andhospitals to facilitate early recognitionand carefully monitor IV rehydration.

Priorities during initial patient con-tact are to establish whether a patient hasdengue, determine the phase of disease(febrile, critical, or recovery), and recog-nize warning signs and/or the presence ofsevere dengue, if present. In addition to aphysical examination, a complete bloodcount in the febrile phase serves seve-ral useful functions if the patient

Table 1. Laboratory findings in the critical phaseof dengue

Hematologic investigationsElevated hematocrit levelLow platelet counts (�100,000 cells/mm3)Progressive leukopenia with atypical

lymphocytesAbnormal coagulation profile

Biochemical investigationsHypoalbuminemiaElectrolyte disturbances (hyponatremia)Metabolic acidosisElevated liver enzyme levels

Imaging featuresThickened gall bladder wallPleural effusions, right more frequent than

leftAscites

94 Pediatr Crit Care Med 2011 Vol. 12, No. 1

progresses to the critical phase: knowl-edge of the patient’s baseline Hct levelcan provide early information indicatingonset of plasma leak, can quantitate theextent of plasma loss, is a good guide tofluid replacement, and, in conjunctionwith other signs, can indicate occultblood loss (2).

Most patients with DF and DHF can bemanaged without hospitalization pro-vided they are alert, there are no warningsigns or evidence of abnormal bleeding,their oral intake and urine output aresatisfactory, and the caregiver is educatedregarding fever control and avoiding non-steroidal anti-inflammatory agents and isfamiliar with the course of illness. A den-gue information/home care card that em-phasizes danger/warning signs is impor-tant (2). These patients need daily clinicaland/or laboratory assessment by traineddoctors or nurses until the danger periodhas passed. For a more detailed guide tooutpatient assessment and monitoring,the reader may refer to the 2009 WHO/Tropical Disease Research document onDengue (2).

If dengue is suspected or confirmed,disease notification to public health au-thorities is important so that preventivemeasures may be set into motion.

Indications for hospitalization and IVfluids include “warning signs” (Fig. 2) ofsignificant plasma leak, of which severe,intense abdominal pain is considered themost important; other warning signs arepersistent vomiting, restlessness or leth-argy, clinical fluid accumulation, muco-sal or other significant bleeds, lethargy orrestlessness, and a rise in Hct level, alongwith a rapid decrease in platelet count (2,28). Infants and patients with comorbidconditions such as diabetes, renal failure,or obesity may also require admission.

Indications for intensive care unit ad-mission include children with severe den-gue manifesting with shock, respiratorydistress, abnormal bleeding, or organ fail-ure, e.g., neurologic complications orliver and/or renal dysfunction (1, 2, 38).

The three major priorities of manage-ment of hospitalized patients with den-gue in the critical phase are replacementof plasma losses, early recognition andtreatment of hemorrhage, and preventionof FO.

Replacement of Plasma Losses—Goals of Fluid Management in Dengue.IV rehydration is the single most impor-tant intervention that can correct shockand save lives in both severe and nonse-vere forms of dengue, provided it is

timely and appropriate. Yet, the seem-ingly simple task of getting the pre-scribed fluid “just right” is often chal-lenging, demands the highest level ofclinical judgment, and is ultimately thekey that differentiates a good vs. bad out-come in sick children with dengue. Inresource-limited, tropical areas of theworld in which dengue outbreaks aremost common, intensive care facilitiesfor monitoring and treatment of shockand respiratory failure may be unavail-able (56). The goals of treatment of den-gue shock are necessarily two-prongedand include both early recognition andreversal of shock and simultaneouslyavoiding FO and the consequent need forventilation by using simple monitoringtools (57–59). These goals may be facili-tated by aiming to restore a minimallyacceptable circulating volume that is ad-equate to establish perfusion to vital or-gans and avoid hemorrhage and multior-gan failure (2, 57–59). In addition, serialmonitoring and correction of coexistinghypoglycemia, hypocalcemia, and elec-trolyte abnormalities are important.

Titrating fluid therapy in dengue.Fluid therapy in a patient with dengueshock has two parts: initial, rapid fluidboluses to reverse shock followed by ti-trated fluid volumes to match ongoinglosses (2). However, for a patient who haswarning signs of plasma leakage but isnot yet in shock, the initial fluid bolusesmay not be necessary (Table 2).

The best methods for titrating fluidtherapy and detecting early signs of hem-

orrhage are repeated, meticulous, clinicalevaluation in conjunction with analysis ofserial Hct trends by experienced caregiv-ers. Sophisticated invasive monitoring israrely necessary unless patients arrivelate with established shock. The endpoints/targets of fluid administration arenormalization of the systolic BP (if low)and obtaining a pulse pressure of �30mm Hg, a urine output of �0.5–1 mL/kg/hr with stable vital signs, and a grad-ual decrease in the elevated baseline Hctlevel (1, 2, 57–59). Monitoring hourlyurine output serves two important goals:an output of 0.5–1.0 mL/kg/hr with stablevital signs indicates shock reversal andensures a minimal acceptable circulatingvolume, whereas an output of �1.5–2mL/kg/hr may be the earliest indicator ofoverhydration/FO with the potential riskof respiratory insufficiency (59) (Table 3).Similarly, assessing two Hct values at4-hr intervals in conjunction with thecirculatory status will provide valuableclues. A high or increasing Hct level in-dicates the need for increased volumes ofcrystalloids if the patient has unstablehemodynamics, whereas in a stable pa-tient, an experienced clinician may electto monitor the patient closely withoutincreasing fluid rates. Likewise, a low or“normal” Hct level in conjunction withshock may be an important indicator ofoccult hemorrhage and the need for ur-gent blood transfusion, whereas in a sta-ble patient in the recovering phase,prompt cessation of IV fluids is the mostimportant action indicated (2).

The critical phase of plasma loss maycontinue for 24 – 48 hrs, necessitatingconstant, careful titration of fluid admin-istration tailored to the clinical status,Hct level, and urine output for this period(2, 56–58). A detailed flowchart recordinghourly vital signs, fluid balance, circula-tory status, and Hct level is essential.

Table 2 and Figures 4 and 5 suggest anapproach for treating dengue with warn-ing signs and dengue with compensatedshock and hypotensive shock, respec-tively. Figure 6 outlines the approach tolate presenters with established shock,and Table 3 provides suggestions for con-trolled fluid resuscitation in dengueshock syndrome (DSS) while at the sametime attempting to prevent/minimize FO.

Differences between DSS and septicshock. Compared to children with septicshock, who often require rapid, large-volume fluid resuscitation (60), there aremajor differences both in the rates andvolumes of fluid resuscitation for dengue

Table 2. Volume-replacement flowchart for pa-tients with dengue with “warning signs”

● Assess airway and breathing and obtainbaseline Hct level

● Commence fluid resuscitation with normalsaline/Ringer’s lactate at 5–7 mL/kg over 1–2hrs

● If hemodynamics and Hct level are stable,plan a gradually reducing IVF regimen

● Titrate fluids on the basis of vital signs,clinical examination, urine output (aim for0.5–1 mL/kg/hr), and serial Hct level

● IVFs, 5–7 mL/kg/hr for 1–2 hrs, then:● Reduce IVFs to 3–5 mL/kg/hr for 2–4 hrs;● Reduce IVFs to 2–3 mL/kg/hr for 2–4 hrs● Continue serial close clinical monitoring and

every 6–8 hourly Hct level● Oral rehydration solutions may suffice when

vomiting subsides and hemodynamicsstabilize

● A monitored fluid regimen may be requiredfor 24–48 hrs until danger period subsides

Hct, hematocrit; IVF, intravenous fluid.

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shock. Wills et al (57) have used muchlower fluid resuscitation rates in �500patients with DSS, and these restrictedvolumes were successful in not only re-versing shock but also minimizing com-plications of FO, including the need forassisted ventilation. The authors reportedmortality rates in the range of 0.2% withslow fluid-filling at rates of 25 mL/kg overthe first 2 hrs. Although there is no evi-dence that colloids are superior to crys-talloids for resuscitation, colloids are of-ten used for severe dengue shock (2, 57).The significant differences in fluid resus-citation volumes for septic vs. dengueshock may probably relate to the fact thatpatients with dengue shock are vasocon-stricted with a narrow pulse pressure asopposed to the predominantly vasodilatedstates in septic shock (2, 59).

When can IV hydration be discontin-ued? Cessation of IV fluids is importantfor preventing FO and can be considered24–48 hrs after defervescence when thehemodynamics, Hct level, and urine out-put are stable, despite minimal IV fluids,especially if the patient is tolerating oralfluids.

Recognition and Management ofHemorrhage. Early detection of signs ofhemorrhage, especially when the losses areinternal, is important. Failure to recognizeand treat occult hemorrhage on an emer-gent basis is one of the most important yetpreventable causes of death (2). Hemor-rhage should be considered in the criticalphase of dengue when the Hct level is “nor-mal” or lower than expected for the degreeof shock or the hemodynamics fails to nor-malize despite the initial 40–60 mL/kg ofcrystalloids/colloids (2).

Clinical features of significant hemor-rhage may be subtle and include increasein tachycardia, abdominal distensionand/or tenderness, stress-induced leuko-cytosis (instead of the characteristic leu-kopenia), agitation/lethargy, acidosis, andevidence of worsening organ function (2).Frank hypotension with dengue usuallyindicates significant hemorrhage but is alate manifestation, and blood transfusionshould be initiated emergently before thisoccurs. The most important interventionfor a patient with dengue shock and life-threatening bleeding is restoration of ox-ygen-carrying capacity with fresh wholeblood (WB) or packed red blood cell(PRBC) transfusions; this must be doneemergently rather than waiting for the Hctlevel to decrease significantly. The 2009WHO dengue guidelines emphasize that,in a bleeding patient with dengue, the

Figure 4. Volume-replacement flowchart for patients with severe dengue and compensated shock. IV,intravenous.

Table 3. Guidelines for reversing dengue shock while minimizing fluid overload

1. Severe dengue with compensated shock: Stabilize airway and breathing, obtain baseline Hctlevel, initiate fluid resuscitation with NS/RL at 5–10 mL/kg over 1 hr, and insert urine catheterearly.

2. Severe dengue with hypotension: Stabilize airway and breathing, obtain baseline Hct level,initiate fluid resuscitation with 1–2 boluses of 20 mL/kg NS/RL or synthetic colloid over 15–20mins until pulse is palpable, slow down fluid rates when hemodynamics improve, and repeatsecond bolus of 10 mL/kg colloid if shock persists and Hct level is still high.

3. Synthetic colloids may limit the severity of fluid overload in severe shock.4. End points/goals for rapid fluid boluses: Improvement in systolic BP, widening of pulse

pressure, extremity perfusion and the appearance of urine, and normalization of elevated Hctlevel.

5. If baseline Hct level is low or “normal” in presence of shock, hemorrhage likely to haveworsened shock, transfuse fresh WB or fresh PRBCs early.

6. After rapid fluid boluses, continue isotonic fluid titration to match ongoing plasma leakage for24–48 hrs; after shock correction, if patient not vomiting and is alert, oral rehydration fluidsmay suffice to match ongoing losses.

7. Check Hct level hourly to twice hourly for first 6 hrs, and decrease frequency as patientimproves.

8. Goals for ongoing fluid titration: Stable vital signs, serial Hct measurement showing gradualnormalization (if not bleeding), and low normal hourly urine output are the most objectivegoals indicating adequate circulating volume; adjust fluid rate downward when this is achieved.

9. Plasma leakage is intermittent even during the first 24 hrs after the onset of shock; hence,fluid requirements are dynamic.

10. Targeting a minimally acceptable hourly urine output (0.5–1 mL/kg/hr) is an effective andinexpensive monitoring modality that can signal shock correction and minimize fluid overload.

11. A urine output of �1.5–2 mL/kg/hr should prompt reduction in fluid infusion rates, providedhyperglycemia has been ruled out.

12. Separate maintenance fluids are not usually required; glucose and potassium may beadministered separately only if low.

13. Hypotonic fluids can cause fluid overload; also, avoid glucose-containing fluids, such as 1/2GNS (GNS or I/2 GNS): the resultant hyperglycemia can cause osmotic diuresis and delaycorrection of hypovolemia.

14. Commence early enteral feeds when vital signs are stable, usually 4–8 hrs after admission.15. All invasive procedures (intubation, central lines, and arterial cannulation) must be avoided; if

essential, they must be performed by the most experienced person. Orogastric tubes arepreferred to nasogastric tubes.

16. Significant hemorrhage mandates early fresh WB or fresh PRBC transfusion; minimize/avoidtransfusions of other blood products, such as platelets and fresh-frozen plasma unless bleedingis uncontrolled despite 2–3 aliquots of fresh WB or PRBCs.

NS/RL, normal saline/Ringer’s lactate; Hct, hematocrit; BP, blood pressure; WB, whole blood;PRBC, packed red blood cell; GNS, 5% glucose in normal saline; 1⁄2 GNS, 5% glucose in 1⁄2 normal saline.

96 Pediatr Crit Care Med 2011 Vol. 12, No. 1

threshold for PRBCs/WB must be higherthan that suggested for septic shock, forwhich an Hct level of �30% is the usualtransfusion threshold (2, 60). This is be-cause hemorrhage with dengue is most of-ten preceded by a background of protractedshock due to plasma leak, which results inthe characteristic elevated Hct level.

Correction of shock with two or morealiquots of fresh WB/PRBCs usuallybreaks the vicious cycle of acidosis, hypo-perfusion, and disseminated intravascu-lar coagulation by restoring circulatingvolume and improving tissue oxygen de-livery (2). This should be administered ina controlled fashion to prevent FO. Ad-ministration of other blood components,such as platelets, fresh-frozen plasma, orcryoprecipitate, may contribute to vol-ume overload and are not as important asfresh WB or PRBCs (2) unless the bleed-ing is ongoing despite 2–3 aliquots ofblood transfusion. It is also important toremember that preventive platelet trans-fusion is unlikely to decrease the inci-dence of significant bleeding (61). Otherinfrequently reported interventions forpatients with bleeding and refractorythrombocytopenia are IV anti-D immu-noglobulin 250 IU/kg (62), IV immuno-globulin (63), and recombinant acti-vated factor VII (64); all these therapiesare expensive, not proven to be of clin-ical benefit, and not currently recom-mended (2).

Although the two most importantcauses of persistent or recurrent shock

are uncorrected hypovolemia due to on-going plasma leakage and hemorrhage,other infrequent causes of persistentshock are myocardial dysfunction and ab-dominal compartment syndrome (ACS),the latter may be encountered in latepresenters (38, 44).

Myocardial dysfunction in dengue ismost often a secondary phenomena dueto the detrimental adaptive phenomenaof prolonged uncorrected hypovolemicshock (e.g., excessively elevated systemicvascular resistance causing coronaryischemia) that may be further aggravatedby high doses of inotropes/pressors. Al-though primary myocardial dysfunction,including both systolic and diastolic dys-function, has been described in childrenwith dengue (31, 41–43), it is an uncom-mon entity and is much less frequent inDSS compared to septic shock (58). Care-givers must desist from overzealous pre-scriptions of inotropes, because theseagents can paradoxically worsen theshock state, especially if hypovolemia isstill uncorrected. Inotrope/pressor sup-port may occasionally be indicated in latepresenters with dengue shock when fea-tures of low cardiac output persist, de-spite having received 40–60 mL/kg offluid and correction of blood loss, i.e.,patients with fluid/blood transfusion re-fractory shock in whom myocardial dys-function is suspected or confirmed byechocardiography (if resources and ex-pertise are available) (Fig. 6). Inotropesmust be ceased if tachycardia or the

shock state worsens after initiation. Pres-sors may also be indicated before intuba-tion of a patient with dengue shock, be-cause some patients may havecatastrophic decompensation during thisperiod.

Indications for Central Venous Pres-sure Monitoring. Central venous pressuremonitoring has limited utility for DSSand is seldom indicated except in latepresenters (Fig. 6). The risks of centralvenous catheter insertion are usuallygreater than the benefits, but if shockpersists despite 40–60 mL/kg fluids andcorrection of suspected hemorrhage, anexperienced operator may consider inser-tion of a central venous catheter. Ultra-sound-guided placement, if available, willminimize complications (2).

FO in Severe Dengue. Apart fromplasma leak and hemorrhage, the thirdmajor management issue in the criticalphase of dengue relates to FO and pul-monary edema (PE). IV rehydration is thesheet anchor of shock therapy; however, asignificant proportion of the adminis-tered fluid will inevitably leak out of thevascular compartment with worse edema,fluid collections, and respiratory insuffi-ciency. Overhydration and pathologicfluid collections can easily occur if morefluid than that sufficient to maintain aminimal acceptable circulating volume isprescribed. Apart from PE, overzealousfluid administration can also cause tenselarge-volume ascites, which may lead toACS (1, 38). Strategies for preventingFO/PE include avoiding prophylacticblood product transfusions in nonbleed-ing patients (even if thrombocytopeniaand coagulopathy are significant) (2, 6,61). Also important is prompt cessationof IV fluids during the recovery phase,because resorption of the leaked plasmaoccurs during this period and extraneousIV fluid can easily worsen FO, precipitatePE, and large pleural and/or ascitic col-lections (2).

Despite these strategies, some patientsmay develop hypoxemic respiratory failurewith respiratory distress and need positive-pressure ventilation, including nasal con-tinuous positive airway pressure (64).

Treatment of Established FO: Diuret-ics and Peritoneal Dialysis. Postresusci-tation fluid-removal strategies, such asdiuretic infusions, should not be neces-sary at all if fluid resuscitation was donejudiciously; however, on occasion, furo-semide boluses, continuous infusions,and even peritoneal dialysis have beenused (44). The decision to administer di-

Figure 5. Suggested approach to a patient with severe dengue and hypotension. NS/RL, normalsaline/Ringer’s lactate.

97Pediatr Crit Care Med 2011 Vol. 12, No. 1

uretics to a patient with dengue and FOrequires considerable judgment, becausediuretics can easily worsen the circula-tory status in children who are still in thecritical phase of plasma leakage (2). If thecritical period has passed as demon-strated by a stable Hct level, stable hemo-dynamics, and a good urine output de-spite minimal IV fluids, a patient withfeatures of FO/PE may be cautiously com-menced on a diuretic infusion at 0.1 mg/kg/hr (2). Any hemodynamic deteriora-tion should prompt immediate cessationof the diuretic infusion.

Peritoneal dialysis has been used forpatients with oliguric renal failure or di-uretic-resistant FO and for patients withACS (38, 44) but may provoke bleedingand should rarely be necessary.

Complications and Management Is-sues in Late Presenters With EstablishedShock. Late presenters often have a dif-ferent and difficult course with refractoryshock; catastrophic, uncontrollable hem-

orrhage and significant fluid collections;a higher prevalence of multiorgan failure;and the need for invasive and expensiveintensive care unit monitoring and ther-apy (Fig. 6) (38). It is this group that mayhave myocardial dysfunction and pleuraland ascitic collections, including ACS,that may worsen both respiratory and cir-culatory status (38, 44). Myocardial dys-function in this group is usually attribut-able to prolonged coronary ischemia,which may be worsened by cat-echolamines; invasive hemodynamicmonitoring in conjunction with serialechocardiography may aid in streamlin-ing therapy (Fig. 6). ACS can set off avicious cycle due to a combination oflarge-volume ascites and ischemic edem-atous gut in conjunction with positive-pressure ventilation (35, 65).

Controlled drainage of ascites may re-sult in improved hemodynamics (66, 67)but must be performed with great caution,because hemorrhagic complications can

occur (2, 67); prevention of ACS by earlyrecognition of shock and judicious fluidadministration remains the best policy.

Complications of aggressive invasiveintensive care unit interventions maylead to significant morbidity and mortal-ity in sick, bleeding children with den-gue, although these have been seldomreported. Catastrophic bleeding may re-sult from intensive care unit practices,such as insertion of invasive central andarterial catheters and intubation. Otherpotentially risky invasive care practicesare rapid drainage of large-volume pleu-ral and ascitic fluid collections during thecritical phase of plasma leakage, whichcan often result in sudden worsening ofthe hemodynamic status and catastrophichemorrhage (67). Judicious IV hydrationwill minimize large-volume effusions andmay completely obviate the need for thethoracic and/or abdominal paracentesiswith its attendant complications (2).

Other Interventions for DHF/DSS. Nodrugs are useful for treating shock indengue. Serum cortisol levels are high inchildren with dengue shock (68), whichsupports a Cochrane database review inwhich the authors stated that there is nogood-quality evidence that corticoste-roids are helpful for DSS (69).

Experienced clinicians can minimizedengue deaths with simple inexpensivestrategies that focus on:

● early recognition of plasma leakage andshock by an educated front-line work-force;

● early institution of a tightly controlledIV rehydration regimen with isotonicfluids;

● ongoing titration of fluid therapy basedon serial monitoring of vital signs,urine output, and Hct level;

● early recognition of the occult hemor-rhage and replacement with fresh WB/PRBCs;

● measures to prevent FO, includingprompt cessation of IV fluid when theperiod of plasma leakage has ceasedand avoiding preventive transfusionwith platelets, fresh-frozen plasma, andother blood products; and

● minimizing iatrogenic interventionsthat may cause complications (naso-gastric tubes, central venous pressureinsertion, pleural and ascitic fluiddrainage).

Prognosis

Although mortality from dengue rangesfrom �1% to 5% (2, 8, 9, 57), mortality

Figure 6. Suggested approach to severe dengue and refractory shock (late presenters). CPAP,continuous positive airway pressure.

98 Pediatr Crit Care Med 2011 Vol. 12, No. 1

from severe dengue shock can be muchhigher, up to 26%, especially in instances ofprofound shock and hemorrhage and whentreatment is delayed (70).

Prevention and FutureDirections

Public health measures for curtailingthis disease are presently focusing on pre-ventive strategies that include measuresfor mosquito control and the develop-ment of vaccines (9, 71). However, pre-vention of dengue remains elusive, be-cause control of the Ae. aegypti mosquitois costly and often ineffective and, hence,has not met with much success, similarto vaccine development (72). However,results of clinical field tests with live at-tenuated tetravalent vaccines have indi-cated encouraging preliminary data inThai adults and children (73).

Summary and Conclusion

Infections with DVs result in a spec-trum of responses, from a mild, undiffer-entiated, self-limited febrile illness to se-vere dengue, which can have a highmortality rate if detected late or treatedinappropriately. The diagnosis of acuteDV infection is based mainly on clinicalsigns and symptoms in endemic coun-tries.

In dengue-epidemic regions, mortalityrates of �1% are achievable when highlytrained caregivers at all levels are tunedto three aspects of management: a thor-ough understanding of the unpredictableand dynamic nature of the disease; earlyrecognition of warning signs and occulthemorrhage; and continuously monitor-ing the patient and titrating interven-tions to match the rapidly evolving clin-ical status.

ACKNOWLEDGMENTS

We are grateful for the detailed anal-ysis and insightful comments of Dr. In-dumathy Santhanam and Dr. ShanthiSangaredddy, assistant professors ofemergency medicine and intensive carefrom the Institute of Child Health(Chennai, India), and Dr. Shrishu Ka-math and Dr. Gayathri Subramaniam,junior consultants from Apollo Chil-dren’s Hospital (Chennai).

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